PARP Inhibitors in the Management of Ovarian Cancer: ASCO Guideline

William P Tew; Christina Lacchetti; Annie Ellis; Kathleen Maxian; Susana Banerjee; Michael Bookman; Monica Brown Jones; Jung-Min Lee; Stéphanie Lheureux; Joyce F Liu; Kathleen N Moore; Carolyn Muller; Patricia Rodriguez; Christine Walsh; Shannon N Westin; Elise C Kohn

doi:10.1200/JCO.20.01924

. Author manuscript; available in PMC: 2022 Mar 23.

Published in final edited form as: J Clin Oncol. 2020 Aug 13;38(30):3468–3493. doi: 10.1200/JCO.20.01924

PARP Inhibitors in the Management of Ovarian Cancer: ASCO Guideline

William P Tew ¹, Christina Lacchetti ², Annie Ellis ^3,⁴, Kathleen Maxian ⁵, Susana Banerjee ⁶, Michael Bookman ⁷, Monica Brown Jones ⁸, Jung-Min Lee ⁹, Stéphanie Lheureux ¹⁰, Joyce F Liu ¹¹, Kathleen N Moore ¹², Carolyn Muller ¹³, Patricia Rodriguez ¹⁴, Christine Walsh ¹⁵, Shannon N Westin ¹⁶, Elise C Kohn ⁹

PMCID: PMC8942301 NIHMSID: NIHMS1780812 PMID: 32790492

Abstract

PURPOSE

To provide recommendations on the use of poly(ADP-ribose) polymerase inhibitors (PARPis) for management of epithelial ovarian, tubal, or primary peritoneal cancer (EOC).

METHODS

Randomized, controlled, and open-labeled trials published from 2011 through 2020 were identified in a literature search. Guideline recommendations were based on the review of the evidence, US Food and Drug Administration approvals, and consensus when evidence was lacking.

RESULTS

The systematic review identified 17 eligible trials.

RECOMMENDATIONS

The guideline pertains to patients who are PARPi naïve. All patients with newly diagnosed, stage III-IV EOC whose disease is in complete or partial response to first-line, platinum-based chemotherapy with high-grade serous or endometrioid EOC should be offered PARPi maintenance therapy with niraparib. For patients with germline or somatic pathogenic or likely pathogenic variants in BRCA1 (g/sBRCA1) or BRCA2 (g/sBRCA2) genes should be treated with olaparib. The addition of olaparib to bevacizumab may be offered to patients with stage III-IV EOC with g/sBRCA1/2 and/or genomic instability and a partial or complete response to chemotherapy plus bevacizumab combination. Maintenance therapy (second line or more) with single-agent PARPi may be offered for patients with EOC who have not received a PARPi and have responded to platinum-based therapy regardless of BRCA mutation status. Treatment with a PARPi should be offered to patients with recurrent EOC that has not recurred within 6 months of platinum-based therapy, who have not received a PARPi and have a g/sBRCA1/2, or whose tumor demonstrates genomic instability. PARPis are not recommended for use in combination with chemotherapy, other targeted agents, or immune-oncology agents in the recurrent setting outside the context of a clinical trial. Recommendations for managing specific adverse events are presented. Data to support reuse of PARPis in any setting are needed.

EDITOR’S NOTE

This American Society of Clinical Oncology (ASCO) Clinical Practice Guideline provides recommendations, with comprehensive review and analyses of the relevant literature for each recommendation. Additional information, including a supplement with additional evidence tables, slide sets, clinical tools and resources, and links to patient information at www.cancer.net, is available at www.asco.org/gynecologic-cancer-guidelines.

INTRODUCTION

In 2020, it is estimated that there will be 21,750 new cases of ovarian cancers diagnosed in the United States, and despite advances in treatment, an estimated 13,940 women will die of the disease.¹ A woman’s risk of getting ovarian cancer during her lifetime is approximately 1 in 78 and her lifetime chance of dying of ovarian cancer is about 1 in 108.¹ Approximately 85%–90% of all ovarian cancers are epithelial in origin, and approximately 70% of all epithelial ovarian cancers are high-grade serous (HGS) adenocarcinoma.² Despite initial therapy, usually consisting of surgical cytoreduction and platinum-taxane combination therapy, the majority of women with advanced-stage epithelial ovarian, tubal, or primary peritoneal cancer (hereinafter referred to as EOC), will have a relapse of their disease and require additional treatment.³

Germline alterations in breast cancer 1 (gBRCA1) and breast cancer 2 (gBRCA2) genes have been identified in up to 17% of women diagnosed with EOC, and somatic mutations are found in an additional 7%.^4–7 Approximately 41%–50% of EOCs are estimated to exhibit homologous recombination deficiency (HRD) involved in repair of DNA damage and replication.⁸ The introduction of poly(ADP-ribose) polymerase inhibitors (PARPis) has led to major change in the approaches to EOC management across the treatment life cycle. In 2014, the US Food and Drug Administration (FDA) approved the first PARPi, olaparib, as a treatment of gBRCA EOC for patients who had received ≥ 3 prior lines of chemotherapy. Rucaparib received FDA approval for treatment of g/sBRCA recurrent disease in 2016. Approval for niraparib and, subsequently, olaparib as maintenance therapy for women with complete or partial response to platinum-based chemotherapy was granted in 2017. Since then, the FDA has expanded the regulatory approval of PARPis, thereby allowing more patients to benefit from these agents and access the drugs earlier in treatment. Recent studies have confirmed that the efficacy of PARPis is enhanced not only in g/sBRCA EOC but also in cancers in which HRD is caused by other underlying etiologies. The applications of PARPis in the management of EOC are complex and all approvals to date are predicated on the absence of prior exposure to PARPis.

The purpose of this guideline is to provide clinicians, other health care practitioners, patients, and caregivers with recommendations regarding the role of PARPis in the management of EOC based on the best available evidence.

GUIDELINE QUESTIONS

This clinical practice guideline addresses five overarching clinical questions:

Should PARPi therapy for EOC be repeated over the course of treatment?
In which patients with newly diagnosed EOC are PARPis recommended?
- 2a.
  What are the histologic types of EOC for which PARPis are recommended?
- 2b.
  What are the biomarker subsets for which PARPis are recommended?
Is PARPi monotherapy recommended for recurrent EOC? If so:
- 3a.
  In which settings (eg, second-line maintenance or treatment of recurrent disease)?
- 3b.
  At what dose and duration?
Are there settings where PARPis in combination with chemotherapy or other targeted therapy are recommended?
How should clinicians manage the specific toxicities of the various PARPis?

METHODS

Guideline Development Process

This systematic review-based guideline was developed by a multidisciplinary Expert Panel, which included two patient representatives and an ASCO guidelines staff member with health research methodology expertise (Appendix Table A1, online only). The Expert Panel met in person, via teleconference, and/or webinar, and corresponded through e-mail. Based on the consideration of the evidence and FDA regulatory approval, the authors were asked to contribute to the development of the guideline, provide critical review, and finalize the guideline recommendations. The guideline recommendations were sent for an open comment period of 2 weeks, allowing the public to review and comment on the recommendations after submitting a confidentiality agreement. These comments were taken into consideration while finalizing the recommendations. Members of the Expert Panel were responsible for reviewing and approving the penultimate version of the guideline, which was then circulated for external review, and submitted to Journal of Clinical Oncology (JCO) for editorial review and consideration for publication. All ASCO guidelines are ultimately reviewed and approved by the Expert Panel and the ASCO Clinical Practice Guidelines Committee before publication. All funding for the administration of the project was provided by ASCO.

The recommendations were developed by using a systematic review of the literature conducted in PubMed for randomized controlled trials (RCTs) published from January 1, 2009, to May 3, 2019. The search was then updated on April 20, 2020, and relevant trials released at ESMO (European Society for Medical Oncology) 2019 and ASCO 2020 were also identified. The FDA’s Center for Drug Evaluation and Research database was also searched for regulatory information. Articles were selected for inclusion in the systematic review of the evidence on the basis of the following criteria:

Population: Adult women with EOC
Intervention: PARPi, including olaparib, niraparib, rucaparib, and veliparib
Comparator: Standard-of-care options or placebo
Outcomes: Therapeutic efficacy (eg, survival, response rate), health-related quality of life, adverse events
Fully published or recent meeting presentations of English-language reports of phase II-III RCTs
For special circumstances, prospective, single-arm trials were accepted.

Articles were excluded from the systematic review if they were (1) editorials, commentaries, letters, news articles, case reports, narrative reviews; or (2) published in a non-English language. The guideline recommendations were crafted, in part, using the Guidelines Into Decision Support (GLIDES) methodology and accompanying BRIDGE-Wiz software.⁹ In addition, a guideline implementability review was conducted. Based on the implementability review, revisions were made to the draft to clarify recommended actions for clinical practice. Ratings for the type and strength of recommendation, evidence, and potential bias are provided with each recommendation.

The ASCO Expert Panel and guidelines staff will work with co-chairs to keep abreast of any substantive updates to the guideline. Based on formal review of the emerging literature, ASCO will determine the need to update. The ASCO Guidelines Methodology Manual (hereafter, Methodology Manual; available at www.asco.org/guidelines-methodology) provides additional information about the guideline update process. This is the most recent information as of the publication date.

Guideline Disclaimer

The Clinical Practice Guidelines and other guidance published herein are provided by the American Society of Clinical Oncology, Inc. (ASCO) to assist providers in clinical decision making. The information herein should not be relied upon as being complete or accurate, nor should it be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. With the rapid development of scientific knowledge, new evidence may emerge between the time information is developed and when it is published or read. The information is not continually updated and may not reflect the most recent evidence. The information addresses only the topics specifically identified therein and is not applicable to other interventions, diseases, or stages of diseases. This information does not mandate any particular course of medical care. Further, the information is not intended to substitute for the independent professional judgment of the treating provider, as the information does not account for individual variation among patients. Recommendations reflect high, moderate, or low confidence that the recommendation reflects the net effect of a given course of action. The use of words like “must,” “must not,” “should,” and “should not” indicates that a course of action is recommended or not recommended for either most or many patients, but there is latitude for the treating physician to select other courses of action in individual cases. In all cases, the selected course of action should be considered by the treating provider in the context of treating the individual patient. Use of the information is voluntary. ASCO provides this information on an “as is” basis and makes no warranty, express or implied, regarding the information. ASCO specifically disclaims any warranties of merchant-ability or fitness for a particular use or purpose. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information, or for any errors or omissions.

Guideline and Conflicts of Interest

The Expert Panel was assembled in accordance with ASCO’s Conflict of Interest Policy Implementation for Clinical Practice Guidelines (“Policy,” found at www.asco.org/rwc). All members of the Expert Panel completed ASCO’s disclosure form, which requires disclosure of financial and other interests, including relationships with commercial entities that are reasonably likely to experience direct regulatory or commercial impact as a result of promulgation of the guideline. Categories for disclosure include employment; leadership; stock or other ownership; honoraria, consulting or advisory role; speaker’s bureau; research funding; patents, royalties, other intellectual property; expert testimony; travel, accommodations, expenses; and other relationships. In accordance with the Policy, the majority of the members of the Expert Panel did not disclose any relationships constituting a conflict under the Policy.

RESULTS

A total of 17 trials^10–27 met eligibility criteria and form the evidentiary basis for the guideline recommendations (Table 1). Outcomes are summarized in Tables 2–5. The identified trials were published between 2011 and 2020 and compared, when comparators were part of the study design, PARPis to standard-of-care options or placebo. The primary outcome for all trials was therapeutic efficacy, expressed as progression-free survival (PFS). Secondary and exploratory outcomes included overall survival (OS), objective response rate, progression-free survival 2, time to discontinuation of treatment or death, time to first subsequent therapy or death (TFST), adverse events (AEs) and health-related quality of life (HRQoL). Characteristics of the studies’ participants are outlined in Table 1. Figure 1 outlines the current approval of PARPis in ovarian cancer.

TABLE 1.

Clinical Trials Evaluating PARPis in EOC

Study (ClinicalTrials.gov identifier)	Patient Population	PARPi	FDA Approval Date	Treatment Dosing	Indication
Front-line maintenance
SOLO1²⁰ (NCT01844986). Phase III, randomized, double-blind, placebo controlled, multicenter study	Female patients with newly diagnosed, histologically confirmed, high-risk advanced (FIGO stage III-IV) BRCAm, HGS or high-grade endometrioid ovarian cancer, primary peritoneal cancer and/or fallopian tube cancer who have completed first-line platinum-based chemotherapy	Olaparib	12/2018	300 mg BID (150 mg, 100 mg tablets)	Deleterious germline OR somatic BRCAm and CR/PR to first-line platinum-based chemotherapy
	Patients must have clinical CR/PR and have no clinical evidence of disease progression
	Patients must be randomly assigned within 8 weeks of their last dose of chemotherapy
PRIMA (Gonzalez-Martin, 2019¹³ NCT02655016). Phase III, randomized, double-blind, placebo controlled, multicenter study	Newly diagnosed advanced ovarian cancer, regardless of BRCAm status	Niraparib	4/2020	300 mg (3 × 100-mg capsules) for patients with a baseline body weight ≥ 77 kg and baseline platelet count ≥ 150,000 µL	CR/PR to first-line platinum-based chemotherapy, regardless of BRCAm or HRD status
	Histologically confirmed, advanced (FIGO stage III or IV), high-grade, predominantly serous or endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have completed first-line platinum-based chemotherapy (neoadjuvant or adjuvant)			200 mg (2 × 100-mg capsules) for patients with a baseline body weight < 77 kg or baseline platelet count < 150,000 µL
	Patient must have clinical CR/PR after completing chemotherapy course
	Patient must be randomly assigned within 12 weeks of the first day of the last cycle of chemotherapy
PAOLA-1²⁴ (NCT02477644). Phase III, randomized, double-blind, placebo controlled, multicenter study	Newly diagnosed ovarian cancer, primary peritoneal cancer, and/or fallopian tube cancer	Olaparib + bevacizumab	5/2020	300 mg BID (2 × 150-mg or 3 × 100-mg tablets)	CR/PR to first-line chemotherapy and bevacizumab combination and g/sBRCA and/or genomic instability by Myriad myChoice CDx
	Histologically confirmed HGS, high-grade endometrioid or other epithelial nonmucinous ovarian cancer in a patient with deleterious germline BRCA1/2 at an advanced stage (FIGO stage IIIB, IIIC, or IV)
	Non-BRCAm patients allowed if HGS
	Completed first-line platinum-taxane chemotherapy with bevacizumab prior to randomization
	Platinum-taxane–based regimen must have consisted of a minimum of four treatment cycles, including platinum, and a maximum of nine
	Bevacizumab dose 15 mg/kg every 3 weeks up to a total of 15 months
	Prior to randomization, patient’s disease must be NED or in CR/PR from her first-line treatment
VELIA¹⁰ (NCT02470585). Phase III, randomized, double-blind, placebo controlled, multicenter study	Histologic diagnosis of FIGO stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal carcinoma, with the appropriate tissue available for histologic evaluation	Veliparib	None to date	150 mg BID for 2 weeks then (transition period) 400 mg BID	Stage III or IV HGS EOC
	HGS adenocarcinoma
	Willing to undergo testing for gBRCA
Treatment of recurrent ovarian cancer
Study 42¹⁴ (NCT01078662). Phase II, open label, nonrandomized, noncomparative, multicenter study	Confirmed germline loss-of-function BRCA1 or BRCA2 mutation deemed deleterious or suspected	Olaparib	12/2014	400 mg BID (50-mg capsules)	Deleterious germline BRCA mutation, ≥ 3 prior systemic therapies
	Platinum-resistant (relapse within 6 months of platinum therapy) epithelial ovarian, primary peritoneal, or fallopian tube cancer (or unsuitable for additional platinum therapy)	Olaparib	12/2014	400 mg BID (50-mg capsules)
	Select patients with breast, pancreatic, and hormone-refractory prostate cancer were also eligible to participate	Olaparib	12/2014	400 mg BID (50-mg capsules)	Deleterious germline BRCA mutation, ≥ 3 prior systemic therapies
Gelmon et al¹² (NCT00679783). Phase II, open label, nonrandomized, noncomparative, multicenter study	Histologically confirmed HGS and/or undifferentiated carcinoma of ovary, fallopian tube, or peritoneum	Olaparib	12/2014	400 mg BID (50-mg capsules)
	Estrogen, progesterone, and HER2-negative advanced adenocarcinoma of the breast	Olaparib	12/2014	400 mg BID (50-mg capsules)	Deleterious germline BRCA mutation, ≥ 3 prior systemic therapies
	Known BRCA-positive breast cancer or ovarian cancer that is not HGS or undifferentiated tubo-ovarian carcinoma	Olaparib	12/2014	400 mg BID (50-mg capsules)
CLIO Study²⁶ (NCT02822157). Phase II, open label, randomized, crossover study	Recurrent epithelial carcinoma of the ovary, fallopian tube, or primary peritoneum	Olaparib	12/2014	400 mg BID (50-mg capsules)	Deleterious germline BRCA mutation, ≥ 3 prior systemic therapies
	At least one previous line of chemotherapy	Olaparib	12/2014	400 mg BID (50-mg capsules)
Liu et al¹⁸ (NCT01116648). Phase II, open label, randomized study	Histologically or cytologically grade 2 or 3 (high-grade) papillary-serous or endometrioid epithelial ovarian cancer, primary peritoneal serous cancer, or fallopian tube cancer;	Olaparib	12/2014	400 mg BID (50-mg capsules)	Deleterious germline BRCA mutation, ≥ 3 prior systemic therapies
	Participants with epithelial ovarian, primary peritoneal, or fallopian tube cancers of other high-grade histologies who carry a known deleterious BRCA germline mutation	Olaparib	12/2014	400 mg BID (50-mg capsules)
Kaye et al¹⁵ (NCT00628251). Phase II, open label, randomized study	Histologically or cytologically confirmed recurrent epithelial ovarian, primary peritoneal, or fallopian tube carcinoma and ≥ 1 measurable lesions according to RECIST	Olaparib	12/2014	400 mg BID (50-mg capsules)	Deleterious germline BRCA mutation, ≥ 3 prior systemic therapies
	Confirmed germline BRCA1/2 mutation, disease that recurred or progressed within 12 months of the most recent platinum-based chemotherapy regimen	Olaparib	12/2014	400 mg BID (50-mg capsules)
SOLO 3²² (NCT02282020). Phase III, open label, randomized, controlled, study	Histologically diagnosed relapsed HGS ovarian cancer (including primary peritoneal and/or fallopian tube cancer) or high-grade endometrioid cancer. Patients are eligible to undergo BRCA testing even if they have not yet had recurrence or progression of disease > 6 months (≥ 183 d) after completion of their last platinum therapy	Olaparib	12/2014	300 mg BID (150-mg tablets)	Deleterious germline BRCA mutation, ≥ 3 prior systemic therapies
	Documented germline mutation in BRCA1 and/or BRCA2 predicted to be deleterious or suspected deleterious
	Patients must have received ≥ 2 prior platinum-based lines of chemotherapy
	Patients must be partially platinum sensitive or platinum sensitive
Study 10¹⁶ (NCT01482715). Phase I/II, open-label, safety, pharmacokinetic, and preliminary efficacy study	Known deleterious BRCA mutation (gBRCA or sBRCA)	Rucaparib	12/2016	600 mg BID (200-mg, 300-mg capsules)	Deleterious germline OR somatic BRCAm and ≥ 2 priors
	Evidence of measurable disease
	Histologically confirmed diagnosis of high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer
	Received ≥ 3 prior chemotherapy regimens and had disease relapse
ARIEL 2²⁵ (NCT01891344). Phase II, open-label, multicenter study	Histologically confirmed diagnosis of HGS or grade 2 or grade 3 endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer. If mixed histology, > 50% of the primary tumor had to be confirmed to be HGS or endometrioid upon rereview by local pathology	Rucaparib	12/2016	600 mg BID (200-mg, 300-mg capsules)	Deleterious germline OR somatic BRCAm and ≥ 2 priors
	Relapsed/progressive disease
	Received prior platinum-based therapy and had platinum-sensitive disease
	Disease had progressed ≥ 6 months after their most recent platinum-based treatment
QUADRA²¹ (NCT02354586). Phase II, multicenter, open-label, single arm study	Tumor HRD testing and blood gBRCAm status testing	Niraparib	10/2019	300 mg daily	Recurrent ovarian cancer treated with ≥ 3 prior chemotherapy regimens and cancer is associated with HRD positivity
	Patients must have histologically diagnosed high-grade (grade 2 or 3) serous epithelial ovarian, fallopian tube, or primary peritoneal cancer with recurrent disease and must have been previously treated with chemotherapy and experienced a response lasting ≥ 6 months to first-line platinum-based therapy
	Patients must have completed three or four previous chemotherapy regimens, with the last chemotherapy regimen > 4 weeks before treatment initiation
	Patients must have measurable disease according to RECIST
	Patients must have formalin-fixed, paraffin-embedded tumor samples available from the primary or recurrent cancer or agree to undergo fresh biopsy before study treatment initiation
Maintenance therapy, second-line and beyond
Study 19^17,28 (NCT00753545). A phase II, randomized, double-blind, placebo controlled, multicenter study	Female patients with histologically diagnosed recurrent ovarian or fallopian tube cancer or primary peritoneal cancer with HGS (grade 2 or 3) features	Olaparib	8/2017	400 mg BID (50-mg capsules)^a	Recurrent ovarian cancer and CR/PR to platinum-based chemotherapy
	Completed ≥ 2 courses of platinum-based chemotherapy and patient’s most recent regimen induced an objective response
	BRCAm status was not required (preplanned retrospective analysis was conducted and published based on BRCAm status)
	Patients must be treated in the study within 8 weeks of completion of their final dose of the platinum-containing regimen
SOLO 2^23,27 (NCT01874353). A phase III, randomized, double-blind, placebo controlled, multicenter study	Recurrent ovarian or fallopian tube or peritoneal cancer	Olaparib	8/2017	300 mg BID (150-mg tablets)^a	Recurrent ovarian cancer and CR/PR to platinum-based chemotherapy
	Platinum-sensitive disease
	Patients had completed ≥ 2 courses of platinum-based chemotherapy with objective response
	Required to have a predicted deleterious, or suspected deleterious, BRCAm based on blood or tumor testing
NOVA¹⁹ (NCT01847274). A phase III, randomized, double-blind, placebo controlled, multicenter study	Histologically diagnosed ovarian cancer, fallopian tube cancer or primary peritoneal cancer	Niraparib	3/2017	300 mg daily (100-mg capsules)	Recurrent ovarian cancer and CR/PR to platinum-based chemotherapy
	HGS (or grade 3) histology or known to have gBRCAm
	Received ≥ 2 previous courses of platinum-containing therapy and had disease that was considered platinum sensitive (> 6 months between penultimate platinum regimen and progression of disease)
	Responded to last the platinum regimen and enrolled within 8 weeks of the last platinum regimen
ARIEL 3¹¹ (NCT01968213). A phase III, randomized, double-blind, parallel assignment, multicenter study	Confirmed diagnosis of HGS or endometrioid epithelial ovarian, primary peritoneal, or fallopian tube cancer	Rucaparib	4/2018	600 mg BID (200-mg, 300-mg capsules)	Recurrent ovarian cancer and CR/PR to platinum-based chemotherapy
	Received ≥ 2 prior platinum-based treatments; last platinum-based regimen must have been administered immediately before maintenance therapy
	Received ≤ 1 nonplatinum chemotherapy regimen. Prior hormonal therapy will not be counted as a nonplatinum regimen
	At least a 6-month disease-free period after prior treatment with the penultimate platinum-based chemotherapy and achieved a response
	For the last chemotherapy course before study entry, patients must have received a platinum-based doublet chemotherapy regimen and have achieved a CR/PR and/or a GCIG CA-125 response

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Abbreviations: BID, twice daily; BRCAm, BRCA mutation; CGIC, Clinical Global Impression of Change; CR, complete response; EOC, epithelial ovarian, tubal, or primary peritoneal cancer; FDA, Food and Drug Administration; FIGO, International Federation of Obstetrics and Gynecology; gBRCAm, germline BRCA mutation; gBRCAwt, germline BRCA wild-type; g/sBRCAm, germline and/or somatic BRCA mutation; HGS, high-grade serous; HRD, homologous recombination deficiency; NED, without evidence of disease; PARPi, PARP inhibitor; PR, partial response; sBRCAm, somatic BRCA mutation.

In an attempt to improve dosing constraints of the capsule formulation, an alternative tablet formulation with improved bioavailability was developed to facilitate olaparib administration to patients. Comparisons of the bioavailability of these two different oral formulations was investigated.²⁹ Study 24 demonstrated that patients’ exposure after tablet doses ≥ 300 mg BID matched or exceeded that of the approved 400-mg BID capsule formulation (8 × 5-mg capsules BID). The 300-mg tablet dose BID was better tolerated than higher doses and it showed similar effectiveness in tumor shrinkage.

TABLE 2.

Newly Diagnosed Maintenance Setting

Outcome	SOLO1²⁰		PRIMA¹³		PRIMA¹³		VELIA¹⁰		VELIA¹⁰		PAOLA-1²⁴
	ITT Set (n = 391)		ITT Set (n = 733)		HRD Population Subset (n = 373)		ITT Set (n = 757)		BRCAm Subset (n = 200)		ITT Set (n = 806)
	Olaparib (n = 260)	Placebo (n = 131)	Niraparib (n = 487)	Placebo (n = 131)	Niraparib (n = 247)	Placebo (n = 126)	Veliparib (n = 382)	Control (n = 375)	Veliparib (n = 108)	Control (n = 92)	Olaparib + Bev (n = 537)	Placebo + Bev (n = 269)
PFS	Data maturity: 51%										Data maturity: 59%
Rate, %	60	27	—	—	—	—	48	34	—	—	52	72
Median PFS, months	NR	13.8	13.8	8.2	21.9	10.4	23.5	17.3	34.7	22.0	22.1	16.6
HR (95% CI)	0.30 (0.23 to 0.41)		0.62 (0.50 to 0.76)		0.43 (0.31 to 0.59)		0.68 (0.56 to 0.83)		0.44 (0.2 8to 0.68)		0.59 (0.49 to 0.72)
Two-sided P	< .001		< .001		< .001		< .001		< .001		< .0001
PFS2	Data maturity: 31%										Data maturity: 39%
Rate, %	75	60	NR		NR		NR		NR		—	—
Median PFS2 (months)	NR	41.9									32.3	30.1
HR (95% CI)	0.50 (0.35 to 0.72)										0.86 (0.69 to 1.09)
Two-sided P	.0002										—
OS	Data maturity: 21%		Interim analysis only								Data maturity: 26%
Rate, %	84	80	84	77%	91	85	NR		NR		NR
Median OS (months)	—	—				—
HR (95% CI)	0.95 (0.60 to 1.53)		0.70 (0.44 to 1.11)		0.61 (0.27 to 1.39)
Two-sided P	—		—
TFST											Data maturity: 59%
Rate, %	—	—	NR		NR		NR		NR		—	—
Median time (months)	51.8	15.1									24.8	18.5
HR (95% CI)	0.30 (0.22 to 0.40)										0.59 (0.49 to 0.71)
Two-sided P	—										< .0001

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Abbreviations: —, not available; Bev, bevacizumab; BRCAm: breast cancer susceptibility gene mutation; HR, hazard ratio; HRD, homologous recombinant deficiency; ITT, intention to treat; NR, not reported; OS, overall survival; PFS, progression-free survival; PFS2, progression-free survival 2; TDT, time to study treatment discontinuation or death; TFST, time to first subsequent therapy or death; TSST, time to second subsequent therapy or death.

TABLE 5.

Grade 3/4 Adverse Events in Randomized Controlled Trials

Reference	Intervention	No. of Patients	Grade 3/4 Adverse Events (%)
Reference	Intervention	No. of Patients	Fatigue^a	Nausea/Vomiting	Anemia^b	Neutropenia^c	Thrombocytopenia
Study 19¹⁷	Olaparib	136	7.3	4.4	5.1	4	NR
Study 19¹⁷	Placebo	129	3.0	< 1	< 1	< 1	NR
SOLO2²³	Olaparib	195	4.1	5.2	19.5	5.1	1
SOLO2²³	Placebo	99	2.0	1.0	2.0	4.0	NR
SOLO1²⁰	Olaparib	260	4	1.1	22	9	1
SOLO1²⁰	Placebo	130	2	1	2	5	2
SOLO3²²	Olaparib	178	4.5	2.2	21.3	9.6	3.9
SOLO3²²	Nonplatinum-based chemotherapy	88	1.3	3.9	0	15.8	2.6
Study 10¹⁶	Rucaparib	42	26.2	14.3	38.1	16.7	2.4
ARIEL 2²⁵	Rucaparib	204	9	6	22	8	2
ARIEL 3¹¹	Rucaparib	372	7	8	19	7	5
ARIEL 3¹¹	Placebo	189	3	2	1	2	0
NOVA¹⁹	Niraparib	367	8.2	4.9	25.3	19.6	33.8
NOVA¹⁹	Placebo	179	0.6	1.7	0	1.7	0.6
PRIMA¹³	Niraparib	484	1.9	2.0	31	12.8	28.7
PRIMA¹³	Placebo	244	0.4	1.6	1.6	1.2	0.4
VELIA¹⁰	Veliparib combination	376	5	8	41	62	31
	Veliparib throughout	377	8	12	38	58	28
	Control	371	3	5	26	49	8
PAOLA-1²⁴	Olaparib + bev	535	5	4	17	6	2
PAOLA-1²⁴	Placebo + bev	267	1	3	< 1	3	< 1

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Abbreviations: bev, bevacizumab; NR, not reported.

Includes patients with fatigue and patients with asthenia.

Includes patients with anemia, decreased hemoglobin, hematocrit, and red blood cell count.

Includes patients with neutropenia; febrile neutropenia; neutropenic sepsis; decreased neutrophil and granulocytes; granulocytopenia.

FIG 1. — PARP inhibitor (PARPi) use opportunities in women who are PARPi naïve. Recommendations are color coded: Orange indicates recommendations; green indicates considerations for use. Figure 1 should not be interpreted as justification for PARPi use in > 1 of these settings. Bev, bevacixumab; CT, carboplatin and paclitaxel; *BRCA*m: *BRCA1/2* mutation.

Study Quality

Study design aspects related to individual study quality, strength of evidence, strength of recommendations, and risk of bias were assessed. Refer to the Methodology Manual for more information and for definitions of ratings for overall potential risk of bias.

Study quality was formally assessed for the fully published trials identified but not for the study only available in abstract form.²⁶ Design aspects related to the individual study quality were assessed by one reviewer, including factors such as blinding, allocation concealment, placebo control, intention to treat (ITT), funding sources, and so forth, and generally indicated a low to intermediate potential risk of bias for most of the identified evidence. In general, the quality of the included studies ranged from intermediate to high. Quality assessment ratings are found in the Data Supplement. Please refer to Methodology Manual for definitions of ratings for overall potential risk of bias.

KEY OUTCOMES OF INTEREST

Efficacy

Newly diagnosed (frontline) maintenance setting.

In the upfront setting, a total of four trials investigated PARPis for maintenance therapy, two as monotherapy^13,20 one as combination therapy,²⁴ and one as combination therapy followed by monotherapy.¹⁰

The SOLO1 trial²⁰ investigated olaparib as first-line maintenance therapy in patients with gBRCA1/2 International Federation of Obstetrics and Gynecology (FIGO) stage III-IV, HGS or endometrioid EOC after a complete response (CR) or partial response (PR) to initial first-line, platinum-based chemotherapy. The trial showed that maintenance with olaparib improved PFS compared with placebo (hazard ratio [HR], 0.30; 95% CI, 0.23 to 0.41). Although the data from secondary outcomes are still immature, they suggest olaparib delays TFST (median, 51.8 months) compared with placebo (median, 15.1 months; TFST HR, 0.30; 95% CI, 0.22 to 0.40).

The PRIMA trial¹³ investigated the efficacy of niraparib maintenance therapy after a response to platinum-based chemotherapy in patients with newly diagnosed, advanced (FIGO stage III-IV), HGS or endometrioid EOC at high risk for relapse. The trial confirmed that the clinical benefit of first-line treatment with niraparib could be extended to all patients with advanced EOC regardless of HRD status, which was used as a stratification factor. In the overall population, a significant benefit in median duration of PFS was seen with niraparib over placebo (13.8 months v 8.2 months; HR, 0.62; 95% CI, 0.50 to 0.76; P < .001). PFS was also significantly improved in those with HRD tumors (21.9 months v 10.4 months; HR, 0.43; 95% CI, 0.31 to 0.59; P < .001). The extended median duration of PFS was also observed in the niraparib group compared with the placebo group (8.1 months v 5.4 months; HR, 0.68) in the subgroup of patients with homologous recombination–proficient tumors.

The PAOLA-1²⁴ trial is the first phase III trial to examine the efficacy of a PARPi with bevacizumab as first-line maintenance therapy in patients with advanced (FIGO stage III-IV), HGS and endometrioid EOC (other histologies if gBRCAm) with CR or PR (CR/PR) to standard platinum-based chemotherapy given with bevacizumab. Patients, who were not restricted by surgical outcome or gBRCA status, were randomly assigned to receive olaparib for up to 24 months and bevacizumab for 15 months in total, or placebo. A statistically significant improvement in PFS was demonstrated in the ITT population compared with placebo (median PFS, 22.1 months v 16.6 months; HR, 0.59; 95% CI, 0.49 to 0.72; P < .0001). Prespecified subgroup analyses showed that patients with sBRCA mutations (HR, 0.31; 95% CI, 0.20 to 0.47) and patients with positive HRD status (including g/sBRCA-mutated tumors; HR, 0.33; 95% CI, 0.25 to 0.45) had the greatest PFS benefits. No benefit was observed in patients with negative HRD status (16.6 v 16.2 months; HR, 1.00; 95% CI, 0.75 to 1.35). The recent approval was limited to women with g/sBRCA and and/or genomic instability by Myriad myChoice CDx (Myriad Genetics, Salt Lake City, UT) and who have had a CR/PR to chemotherapy plus bevacizumab combination.

The VELIA trial¹⁰ assessed the efficacy of veliparib added to first-line chemotherapy with carboplatin and paclitaxel and continued as maintenance monotherapy in patients with previously untreated, advanced, FIGO stage III-IV, HGS EOC. In the overall population, the median PFS was 23.5 months in the induction and maintenance veliparib group compared with 17.3 months in those receiving placebo (HR, 0.68; 95% CI, 0.56 to 0.83; P < .001). In patients with gBRCA mutation, the median PFS was 34.7 versus 22.0 months, respectively, in the veliparib compared with the control group (HR, 0.44; 95% CI, 0.28 to 0.68; P < .001). In the HRD cohort, the corresponding duration was 31.9 months and 20.5 months, respectively (HR, 0.57; 95% CI, 0.43 to 0.76; P < .001). In the ITT population, median PFS was 23.5 months versus 17.3 months, respectively (HR, 0.68; 95% CI, 0.56 to 0.83; P < .001). Stratification was based on gBRCA status and was added 14 months after initiation of the study, at which time the study was more than half accrued. No benefit was seen in patients with homologous-recombination–deficient BRCA wild-type (BRCAwt) disease (HR, 0.74; 95% CI, 0.52 to 1.06) or those with homologous-recombination–proficient disease (HR, 0.81; 95% CI, 0.60 to 1.09). Veliparib is not approved in this setting and is not commercially available at this writing.

Treatment of Recurrence Setting.

Eight studies^{12,14,16,18,21,22,25,26} were identified that investigated PARPis as treatment for recurrence. Four open-label, phase II studies^12,14,18,26 examined olaparib for patients with gBRCAm advanced EOC. Each study found improved clinical benefit with olaparib. Two single-arm studies of rucaparib, ARIEL 2²⁵ and Study 10,¹⁶, also both demonstrated improved PFS in measurable gBRCAm ovarian cancer.

The SOLO3 trial²² assessed the efficacy of olaparib compared with chemotherapy of physician’s choice in patients with platinum-sensitive, relapsed, HGS or endometrioid EOC with gBRCAm. Patients were stratified by type of chemotherapy received, prior lines of chemotherapy (2–3 v ≥ 4), and platinum-free interval (6–12 v > 12 months). The objective response rate (ORR) by independent central review was 72% with olaparib versus 51% with treatment of physician’s choice (odds ratio, 2.53; 95% CI, 1.40 to 4.58; P = .002). The HR for PFS independent central review was 0.62 (95% CI, 0.43 to 0.91; P = .013), with a median of 13.4 months with olaparib versus 9.2 months with chemotherapy. The PFS by investigator assessment was 0.49 (95% CI, 0.35 to 0.70; P < .001), with a median of 13.2 versus 8.5 months, respectively.

The QUADRA trial,²¹ a single-arm nonrandomized trial, evaluated niraparib in adult patients with relapsed, HGS epithelial ovarian, fallopian tube, or primary peritoneal cancer who had been treated with ≥ 3 previous chemotherapy regimens. The trial met its primary end point of overall response, with 13 of 47 patients (28%; 95% CI, 15.6% to 42.6%; one-sided P = .00053) with HRD-positive tumors who received three to four previous anticancer therapies and were sensitive to the most recent platinum-based therapy. The median duration of PFS in this population was 5.5 months (95% CI, 3.5 to 8.2 months), and median duration of response was 9.2 months (95% CI, 5.9–not estimable months). A total of 38 of 456 patients (8%) in the modified per-protocol population achieved an overall response. The observed median OS in the modified per-protocol population was 17.2 months (95% CI, 14.9 to 19.8 months).

Second-line and beyond maintenance setting.

Four trials investigated the efficacy of PARPis in maintenance therapy in recurrent disease.^{11,17,19,23,28}

Study 19¹⁷ accrued patients with platinum-sensitive, recurrent, high-grade EOC who had received ≥ 2 prior lines of platinum-based chemotherapy and had a CR/PR to the most recent treatment, demonstrating olaparib maintenance significantly improved PFS (median 8.4 v 4.8 months; HR, 0.35; 95% CI, 0.25 to 0.49; P < .001). Retrospective testing for g/sBRCA mutations was performed for all patients, and it was determined that 51% of participants had g/sBRCAm. Patients with gBRCAm tumors were reported to have a 6.9-month prolongation of median PFS (11.2 compared with 4.3 months in the olaparib and placebo arms, respectively). Additional analyses in the BRCAwt population also demonstrated a statistically significant difference in favor of the olaparib maintenance treatment arm. However, the magnitude of difference was lower when compared with the population of patients with gBRCAm (7.4 months v 5.5 months; HR, 0.54; 95% CI, 0.34 to 0.85; P = .0075). Analyses for OS²⁸ showed a slight survival advantage with olaparib over placebo in the ITT population (media OS, 29.8 v 27.8 months, respectively; HR, 0.73; 95% CI, 0.55 to 0.95; P = .02) after a median follow-up of 78 months. In the gBRCAm population, OS was 34.9 months versus 30.2 months in the olaparib-treated patients compared with those receiving placebo, respectively. The median improvement in OS was 4.7 months longer for olaparib versus placebo (HR, 0.62; 95% CI, 0.42 to 0.93). It is notable that the threshold was not set to determine statistical significance for OS in the BRCAm subgroup; therefore, the reported P values are nominal.

The SOLO2 trial²³ investigated olaparib monotherapy in patients with platinum-sensitive, recurrent, g/sBRCA1/2m EOC who had received ≥ 2 lines of chemotherapy and demonstrated a CR/PR to the most recent line of treatment. Results showed a statistically significant improvement in the median PFS for olaparib over placebo of 13.6 months (median PFS, 19.1 v 5.5 months), translating to a 70% reduction in risk of disease progression or death with olaparib versus placebo (HR, 0.30; 95% CI, 0.22 to 0.41; P < .0001). The proportion of patients who had not experienced disease progression at 12 months was 3.1 times greater in the olaparib group than in the placebo group (65.1% v 20.9%, respectively). Moreover, the proportion of patients who remained progression free at the 2-year mark was 2.8 times greater in the olaparib group than in the placebo group (43.0% v 15.1%, respectively). A preplanned, final, OS analysis with data maturity of 61% demonstrated that olaparib extended OS by approximately 13 months compared with placebo (38.8 v 51.7 months; HR, 0.74; 95% CI, 0.54 to 1.00; P = .054) in the full analysis set.²⁷ In the prespecified sensitivity analysis of patients with germline BRCA mutation, OS was extended by 15 months with olaparib compared with placebo (37.4 v 52.4 months; HR, 0.71; 95% CI, 0.52 to 0.97; P = .031).²⁷ The NOVA trial¹⁹ evaluated niraparib in patients with platinum-sensitive, recurrent EOC who had a CR/PR after ≥ 2 prior lines of platinum-based chemotherapy. Niraparib maintenance significantly improved PFS, compared with placebo, irrespective of the gBRCAm (21.0 v 5.5 months; HR, 0.27; 95% CI, 0.17 to 0.41; P < .001) or HRD status (HRD plus BRCAwt: 12.9 v 3.8 months; HR, 0.38; 95% CI, 0.24 to 0.59; P < .001) and in the overall BRCAwt group (9.3 v 3.9 months; HR, 0.45; 95% CI, 0.34 to 0.61; P < .001).

The ARIEL 3 trial¹¹ for rucaparib included three populations for step-down analysis of the primary end point, PFS: tumor BRCA-mutant (germline or somatic); HRD-positive, which included the gBRCAm group along with those with a positive HRD score (including BRCAwt with high [≥ 16%] genomic loss of heterozygosity; and the ITT [all-comer] population), which, again, included the gBRCAm and HRD-positive groups.¹¹ PFS was significantly improved with rucaparib versus placebo in all three populations, although the most robust clinical outcomes were seen in the gBRCAm subgroup.

Quality of Life

Seven RCTs^{10,13,17,19,20,23,24} reported quality-of-life (QOL) end points with high completion rates. Analyses of these patient-reported outcomes found, in general, the majority of QOL scores numerically favored treatment with PARPis. However, few significant differences were observed between the treatment groups. In the absence of disease-related symptoms for trials occurring in the maintenance setting, that comparable scores were observed over time across and between treatment groups suggests that women maintain QOL during their PARPi treatment when compared with placebo. PARPis did not appear to incur additional burden or negatively impact HRQoL either during treatment or long-term follow up.

Adverse Events

The proportion of patients who experienced any AEs was higher in patients receiving PARPis than those in the comparator groups (Table 5). Anemia was the most common grade ≥ 3 AE in the PARPi group, reported to range from 5% to 22% with olaparib,^17,20,22,23 19% to 38% with rucaparib,^11,16,25 25% to 31% with niraparib,^13,19 38% to 41% with veliparib combination therapy,¹⁰ and 17% with olaparib plus bevacizumab.²⁴ The incidence of other AEs such as fatigue/asthenia, nausea, and vomiting were much lower (Table 5). Hematologic toxicities were more frequent with veliparib combination and niraparib monotherapy than with treatment with other PARPis. Grade 3 or higher neutropenia occurred in up to 62% of patients receiving veliparib combination treatment¹⁰ and in 19.6% of patient treated with niraparib.¹⁹ Similarly, thrombocytopenia was reported in up to 31% of patients receiving veliparib combination treatment and in 34% of those treated with niraparib. However, in the NOVA trial, thrombocytopenia was transient and treatment discontinuations were not attributed to these hematologic events.¹⁹ The most prominent grade 3/4 AEs with rucaparib included fatigue (26.2%) and nausea and vomiting (14%).¹⁶ Overall, management of AEs, for the majority of cases, were handled with appropriate dose reductions and delays.

RECOMMENDATIONS

NOTE: These recommendations pertain only to patients with EOC who have not previously received a PARPi. The recommendations are based on clinical trial results and FDA approvals and do not necessarily capture regulatory approval in other jurisdictions.

CLINICAL QUESTION 1

Repeating PARPi

Should PARPi therapy for EOC be repeated over the course of treatment?

Recommendation 1.0

Repeating PARPi therapy in the treatment of EOC is not recommended at this time. Consideration should be made as to the best time in the life cycle of an individual patient’s EOC in which to use PARPi; clinical trial participation is encouraged (Type: informal consensus, benefits outweigh harms; Evidence quality: insufficient; Strength of recommendation: strong).

Literature review and analysis.

Trials investigating the redeployment of PARPis are currently underway. Enrollment began in 2017 for the OReO/ENGOT Ov-38 trial (ClinicalTrials.gov identifier: NCT03106987), a randomized, placebo-controlled, multicenter trial of olaparib maintenance retreatment in patients with nonmucinous EOC, and a CR/PR to their most recent platinum-based chemotherapy. Eligibility requires prior receipt of maintenance PARPi therapy. Random assignment to olaparib or matching placebo is split across two cohorts (approximately 416 patients): patients with a known BRCAm in cohort 1; patients with BRCAwt in cohort 2. The primary end point is investigator-assessed PFS and the study is expected to be completed in 2021.

CLINICAL QUESTION 2

Newly Diagnosed Ovarian Cancer

For which patients with newly diagnosed EOC are PARPi recommended?

What are the histologic types of EOC for which PARPis are recommended?
What are the biomarker subsets for which PARPis are recommended?

Recommendation 2.0

PARPis are not recommended for use in initial treatment of early-stage (ie, stage I-II) EOC, because there is insufficient evidence to support use in this population. (Type: informal consensus; benefits outweigh harms; Evidence quality: insufficient; Strength of recommendation: strong)

Recommendation 2.1

Women with newly diagnosed stage III-IV EOC whose disease is in CR/PR to first-line, platinum-based chemotherapy should be offered PARPi maintenance therapy with olaparib (for those with germline or somatic pathogenic or likely pathogenic variants in BRCA1 and BRCA2 genes) or niraparib (all women) for treatment of high-grade serous or endometrioid ovarian cancer.

PARPi maintenance therapy should consist of olaparib (300 mg orally every 12 hours for 2 years) or niraparib (200–300 mg orally daily for 3 years). Longer duration could be considered in selected individuals.

(Type: evidence based, benefits outweigh harms; Evidence quality: high; Strength of recommendation: strong).

Recommendation 2.2

The addition of olaparib to bevacizumab maintenance may be offered to patients who have stage III-IV, high-grade serous or endometrioid ovarian cancer and germline or somatic pathogenic or likely pathogenic variants in BRCA1 or BRCA2 genes and/or genomic instability, as determined by Myriad myChoice CDx, and who have a CR/PR to chemotherapy plus bevacizumab combination (Type: evidence based, benefits outweigh harms; Evidence quality: strong; Strength of recommendation: strong).

Recommendation 2.3

Inclusion of the PARPi veliparib with combination chemotherapy followed by veliparib maintenance therapy cannot be recommended at this time. There are no data that this approach is superior, equal, or less toxic than a switch maintenance (Type: evidence based; benefits/harms ratio unknown; Evidence quality: intermediate; Strength of recommendation: strong).

Note: As of this writing, veliparib is not commercially available.

Literature review and analysis.

The efficacy of PARPi as front-line maintenance therapy has been demonstrated in four randomized trials identified by the systematic review: SOLO1,²⁰ PRIMA,¹³ PAOLA-1,²⁴ and VELIA.¹⁰ Maintenance therapy with PARPi achieved substantial PFS benefit among patients with platinum-sensitive, recurrent ovarian cancer after a CR/PR to the most recent regimen. SOLO1²⁰ demonstrated that, after a CR/PR to first-line platinum-based chemotherapy, olaparib maintenance therapy confers PFS benefits to patients with advanced primary BRCA1/2-mutated ovarian cancer (Table 2). The PRIMA trial,¹³ in which patients newly diagnosed with advanced ovarian cancer were enrolled regardless of their BRCA status, found a significant improvement in PFS compared with placebo in the overall population (Table 2). The PFS benefit was even more pronounced in the HRD-positive patient subgroup. Notably, maintenance with niraparib also demonstrated a significant reduction in the risk of disease progression or death in the HRD-negative subgroup.

Two trials were identified that considered PARPi combination therapy. The PAOLA-1 trial²⁴ investigated the efficacy of maintenance therapy with a PARPi in patients with advanced ovarian cancer regardless of BRCA mutation status who are receiving first-line standard-of-care treatment including bevacizumab. Results demonstrate olaparib added to bevacizumab maintenance treatment significantly improved PFS in the overall population. The benefit was even more pronounced in the BRCA-mutated and HRD-positive subgroups. No statistically significant benefit was seen in patients with HRD-negative tumors (HR, 1.00; 95% CI, 0.75 to 1.35). VELIA¹⁰ evaluated a PARPi, veliparib, in combination with chemotherapy (carboplatin and paclitaxel), followed by PARPi maintenance treatment in the first-line setting. The primary analysis demonstrated a significantly extended PFS in all women, regardless of biomarker status. However, it remains unclear if the addition of veliparib is necessary for the overall benefit, because no chemotherapy-plus-placebo comparator arm was included in the study design.

Clinical interpretation.

All trials reported to date present results for women who were PARPi naïve at the time of initiation of PARPi therapy. The rapid progression of studies examining PARPi for therapy of recurrent disease to second-line maintenance to front-line maintenance limited having a re-exposure scenario. This is an important area of unmet need for investigation. Retreatment off study is strongly discouraged because it is unsupported by data and prevents the capture of data that may be useful to the community. The lack of OS benefit from any of the treatment or maintenance studies to date should be balanced against factors such as the unknown short-term and late risks (eg, acute myeloid leukemia [AML]/myelodysplastic syndromes [MDS]) and development of collateral resistance to other agents (eg, platinum).

Physicians and patients are strongly encouraged to consider the full life cycle of advanced ovarian cancer against current data in determining when to use PARPi for individual care (Fig 1). The evolution of knowledge regarding mechanisms of resistance to PARPi makes clear that parameters defining resistance (eg, minimum treatment-free interval, biomarker selection) may need to be taken into account in clinical testing of PARPi retreatment. This should be done in the context of well-defined clinical trials. The recommendations herein are focused on the use of PARPi for women with ovarian cancer who have not received prior treatment with a PARPi.

Data are strong from all studies indicating that women with gBRCAm (or the rare sBRCAm) have improved PFS with PARPi maintenance therapy with either olaparib or niraparib. The recently published ASCO guideline on germline and somatic tumor testing in epithelial ovarian cancer³⁰ recommends early germline testing. This recommendation recognizes that the identification of a deleterious germline or somatic mutation in BRCA1 or BRCA2 would inform PARPi treatment decisions for women with newly diagnosed disease. The PRIMA study demonstrates progression-free benefit for all women with high-grade serous or endometrioid ovarian cancer. Together, these results support consideration of primary maintenance therapy for all women with high-grade serous or endometrioid disease. However, no OS results are available from these studies nor data to address conservation of platinum-sensitivity in women whose disease progressed while they received PARPi maintenance or after completion of PARPi maintenance. Those results should inform future treatment decision-making. Given the expectation that early treatment may confer the best outcome, maintenance therapy with PARPi should be offered, with these caveats.

Doses recommended are the standard dose used for either maintenance or treatment of existing disease and are shown in Recommendation 2.0 with a qualification in the discussion for Recommendation 5.2. Eligibility for maintenance therapy includes women with CR/PR to initial platinum-based therapy, to continue for up to 2 years (olaparib) or 3 years (niraparib) in women with CRs who are tolerating the drug. Longer treatment duration can be considered for women initiating maintenance therapy with a PR to platinum-based therapy and demonstrating clinical improvement with PARPi treatment. The patient and her physician should consider risk-benefit balance for prolonged therapy. Switching PARPis to address tolerance is acceptable; however, it is not acceptable to switch to a different PARPi at the time of disease progression while being treated with a PARPi.

Inclusion of bevacizumab with primary chemotherapy and as maintenance has been evaluated for women with advanced stage III-IV, newly diagnosed EOC.³¹ It is recognized that not all women with newly diagnosed EOC may have results of a germline test at the initiation or even during primary chemotherapy and may have been initiated on a bevacizumab-containing therapy. Moving to a PARPi maintenance per the FDA approval would then be difficult. The PAOLA-1 trial examined the role of olaparib maintenance added on top of a regimen including bevacizumab with primary chemotherapy and as maintenance. This phase III trial demonstrated benefit with addition of olaparib for women with g/sBRCA and women with HRD score ≥ 42; there was a 0.9-month difference for women with wild-type disease and no evidence of HRD.²⁴ Thus, addition of a PARPi in the setting of a bevacizumab combination primary therapy is a reasonable option for those women who have attained a CR/PR to primary therapy. This recommendation is of moderate strength, because the added value for women with wild-type disease is questionable and may be informed further by the outcome of the ongoing FDA review.

Only the VELIA study included a PARPi with chemotherapy in initial treatment of ovarian cancer.¹⁰ Inclusion of veliparib with chemotherapy and continued into maintenance therapy for 30 cycles may be offered if veliparib becomes commercially available.¹⁰ There are no data, to our knowledge, to demonstrate inclusion during chemotherapy followed by maintenance provides equal to or greater benefit, or reduced toxicity, compared with switch maintenance approaches. Furthermore, long-term safety data for inclusion of veliparib with chemotherapy followed by maintenance are needed, especially to address risk of AML/MDS. Substitution of another PARPi in the VELIA regimen is strongly discouraged, because safety, dose, and duration of niraparib and rucaparib have not been defined. Use of olaparib requires a carboplatin dose modification and attenuation of the olaparib exposure per cycle.^32–34 There are also limited long-term safety data for the olaparib/carboplatin/paclitaxel regimen.³⁴

CLINICAL QUESTION 3

Recurrent Ovarian Cancer: Second-Line or Greater Maintenance and Treatment

Is PARPi monotherapy recommended for recurrent EOC? If so:

In which settings (eg, second-line maintenance or treatment of recurrent disease)?
At what dose and duration?

Recommendation 3.0

PARPi monotherapy maintenance (second-line or more) may be offered to patients with EOC who have not already received a PARPi and who have responded to platinum-based therapy regardless of BRCA mutation status; treatment is continued until progression of disease or toxicity despite dose reductions and best supportive care.

Options include: olaparib 300 mg every 12 hours; rucaparib 600 mg every 12 hours; niraparib 200–300 mg once daily.

(Type: evidence based, benefits outweigh harms; Evidence quality: high; Strength of recommendation: strong)

Recommendation 3.1

Treatment with a PARPi should be offered to patients with recurrent EOC who have not already received a PARPi and have a germline or somatic pathogenic or likely pathogenic variants in BRCA1 or BRCA2 genes.

Options include: olaparib 300 mg every 12 hours; rucaparib 600 mg every 12 hours; niraparib 200–300 mg once daily.

(Type: evidence based, benefits outweigh harms; Evidence quality: high; Strength of recommendation: strong)

Recommendation 3.2

Treatment with a PARPi monotherapy should be offered to patients with recurrent EOC who have not already received a PARPi and whose tumor demonstrates genomic instability, as determined by Myriad myChoice CDx, and has not recurred within 6 months of platinum-based therapy (Type: evidence based, benefits outweigh harms; Evidence quality: high; Strength of recommendation: strong).

Recommendation 3.3

PARPis are not recommended for treatment of BRCAwt or platinum-resistant, recurrent EOC (Type: evidence based, benefits outweigh harms; Evidence quality: high; Strength of recommendation: strong).

Literature review and analysis.

The systematic review identified 13 trials in total, nine of which were open label, phase II studies^{12,14–16,18,21,22,25,26} and four of which were phase II or III controlled trials.^11,17,19,23 In maintenance therapy for the second-line or greater setting, Study 19,^17,28 SOLO2,²³ NOVA,¹⁹ and ARIEL3¹¹ all demonstrated significant efficacy of PARPis compared with placebo (Table 3). For recurrent disease, Study 42,¹⁴ SOLO3,²² Study 10¹⁶, ARIEL2,²⁵ and QUADRA²¹ all reported a significant improvement in response and PFS in patients with BRCA mutations (Table 4).

TABLE 3.

Treatment of Recurrent Ovarian Cancer

Study	Dose and Formulation	Data Cutoff	No. of Patients	Treatment and Comparator	Efficacy Outcomes
Study	Dose and Formulation	Data Cutoff	No. of Patients	Treatment and Comparator	PFS Rate and HR (95% CI) P	Median PFS (months) and HR (95% CI) P	OS Rate and HR (95% CI)	Median OS (months)	ORR% and ORR (95% CI) P
Study 42¹⁴	400 mg BID, capsule	July 2012	Ovarian cancer subset: 193	Olaparib (no comparator)	54.6%	7.0	64.4%	16.6	31.1 ( 24.6 to 38.1)
CLIO²⁶	300 mg BID, tablet	Dec 2018	100	Olaparib v CT^a	NA	Olaparib: 2.9	NA	NA	Olaparib: 18%^b
CLIO²⁶	300 mg BID, tablet	Dec 2018	100	Olaparib v CT^a	NA	CT: 3.4	NA	NA	CT: 6%
Liu et al¹⁸	400 mg BID, capsule	Mar 2014	90	Olaparib + cediranib v olaparib	NA	Olaparib + cediranib: 17.7	NA	NA	NA
						Olaparib: 9.0
						0.42 (0.23 to 0.76)
						P = .005
Gelmon et al¹²	400 mg BID, capsule	Mar 2010	Ovarian cancer subset: 65	Olaparib (no comparator)	NA	BRCAm nonserous: 11.4^c	NA	NA	BRCAm nonserous: 75%
						BRCAm serous: 7.2^c			BRCAm serous: 30.8%
						BRCAwt nonserous: 2.6^c			BRCAwt nonserous: 0%
						BRCAwt serous: 6.3^c			BRCAwt serous: 25.6%
Kaye et al¹⁵	200 or 400 mg BID, capsules	PFS: Sep 15, 2009	97	Olaparib v PLD	0.88 (0.51 to 1.56) .66	Olaparib 200 mg: 6.5 (5.5 to 10.1)	PLD v 200: 0.66 (0.27 to 1.55)	NA	Olaparib 200 mg: 25%
		OS: April 30, 2010				Olaparib 400 mg: 8.8 (5.4 to 9.2)	PLD v 40: 1.01 (0.44 to 2.27)		Olaparib 400 mg: 31%
		OS: April 30, 2010				PLD: 7.1 (3.7 to 10.7)	PLD v 40: 1.01 (0.44 to 2.27)		PLD: 18%
SOLO3²²	300 mg BID, tablets	Oct 2018	266	Olaparib v chemotherapy treatment of physician’s choice	0.62 (0.43 to 0.91) .013	Olaparib: 13.4	NA	NA	Olaparib: 72.2%
						TPC: 9.2			TPC: 51.4%
						TPC: 9.2			2.53 (1.40 to 4.58) .002
Study 10¹⁶	600 mg BID, capsule	Nov 2015	42	Rucaparib (no comparator)	59.5%	7.8	NA	NA	—
ARIEL 2²⁵	600 mg BID, capsule	Jan 2016	206	Rucaparib (no comparator)	BRCAm: 50%	BRCAm: 12.8	NA	NA	BRCAm: 32%
					LOH low: 10%	LOH low: 5.2			LOH low: 7%
					0.27 (0.16 to 0.44) < .0001	LOH high: 5.7			P < .0001
					0.27 (0.16 to 0.44) < .0001	LOH low: 5.2			LOH high: 24%
					LOH high: 28%				LOH low: 7%
					LOH low: 10%				P = .0033
					0.62 (0.42 to 0.90) .011				P = .0033
QUADRA²¹	300 mg, daily	Apr 2018	463	Niraparib (no comparator)	NA	5.5	NA	17.2	28%
QUADRA²¹	300 mg, daily	Apr 2018	463	Niraparib (no comparator)	NA	5.5	NA	17.2	Median duration of response: 9.2 months

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Abbreviations: BID, twice daily; CT, chemotherapy; HR, hazard ratio; LOH, loss of heterozygosity; NA, not available; OR, odds ratio; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin; TPC, treatment of physician’s choice.

Physician’s choice chemotherapy that includes carboplatin + gemcitabine or carboplatin + paclitaxel or carboplatin + liposomal doxorubicin or liposomal doxorubicin every 4 weeks or topotecan or paclitaxel weekly.

ORR for olaparib was 38% (n = 5 of 13) in patients with gBRCAm and 13% (n = 7 of 54) in patients with gBRCAwt.

Median PFS was reported in days and converted to months for the table.

TABLE 4.

Maintenance Therapy for Recurrent Platinum-Sensitive Disease

Outcome	SOLO2^23,27 (tablet formulation, 300 mg BID)		STUDY 19^17,28 (capsule formulation, 400 mg BID)		NOVA¹⁹ (capsule formulation, 300 mg daily)		NOVA¹⁹ capsule formulation, 300 mg daily)		ARIEL 3¹¹ (capsule formulation, 600 mg BID)		ARIEL 3¹¹ (capsule formulation, 600 mg BID)
	DCO Sept 2016/Feb 2020 for OS Full Analysis Set (N = 295)		DCO 2012/2015 BRCAm Subset (n = 136)		DCO June 2016 gBRCAm Subset (n = 203)		DCO June 2016 Non-gBRCAm Subset (n = 350)		DCO April 2017 BRCAm Subset (n = 196)		DCO April 2017 ITT (n = 207)
	Olaparib (n = 196)	Placebo (n = 99)	Olaparib (n = 74)	Placebo (n = 62)	Niraparib (n = 138)	Placebo (n = 65)	Niraparib (n = 234)	Placebo (n = 116)	Rucaparib (n = 130)	Placebo (n = 66)	Rucaparib (n = 141)	Placebo (n = 66)
PFS
Median PFS (months)	19.1	5.5	11.2	4.3	21.0	5.5	9.3	3.9	16.6	5.4	10.8	5.4
HR (95% CI)	0.30 (0.22 to 0.41)		0.18 (0.10 to 0.31)		0.27 (0.17 to 0.41)		0.45 (0.34 to 0.61)		0.23 (0.16 to 0.34)		0.37 (0.30 to 0.45)
Two-sided P	< .0001		< .00001		< .0001		< .001		< .001		< .0001
PFS2
Median PFS2 (months)	NR	18.4	NA	NA	25.8	19.5	18.6	15.6	NA	NA	NA	NA
HR (95% CI)	0.50 (0.34 to 0.72)		NA		0.48 (0.28 to 0.82)		0.69 (0.49 to 0.96)		NA		NA
Two-sided P	.0002		NA		.006		.03		NA		NA
OS
Median OS (months)	51.7	38.8	34.9	30.2	NA	NA	NA	NA	NA	NA	NA	NA
HR (95% CI)	0.74 (0.54 to 1.00)		0.62 (0.41 to 0.94)		NA		NA		NA		NA
Two-sided P	.054		.02480		NA		NA		NA		NA
ORR (CR+PR)
No. of events: total no. of patients (%)	NA	NA	7:57 (12)	2:48 (4)	NA	NA	NA	NA	15:40 (37.5)	2:23 (8.7)	26:141 (18.4)	5:66 (7.6)
HR (95% CI)	NA		3.36 (0.75 to 23.72)		NA		NA		NR		NR
Two-sided P	NA		.12		NA		NA		NR		NR
TDT
Median time (months)	19.4	5.6	11.0	4.6	NA	NA	NA	NA	NA	NA	NA	NA
HR (95% CI)	0.31 (0.23 to 0.42)		0.36 (0.25 to 0.52)		NA		NA		NA		NA
Two-sided P	< .0001 (nominal P value)		< .00001		NA		NA		NA		NA
TFST
Median time (months)	27.9	7.1	15.6	6.2	21.0	8.4	11.8	7.2	NA	NA	NA	NA
HR (95% CI)	0.28 (0.21 to 0.38)		0.32 (0.22 to 0.48)		0.31 (0.21 to 0.48)		0.55 (0.41 to 0.72)		NA		NA
Two-sided P	< .0001		< .00001		< .001		< .001		NA		NA
TSST
Median time (months)	NR	18.2	22.0	15.3	NA	NA	NA	NA	NA	NA	NA	NA
HR (95% CI)	0.37 (0.26 to 0.53)		0.41 (0.28 to 0.62)		NA		NA		NA		NA
Two-sided P	< .0001		.00001		NA		NA		NA		NA

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Abbreviations: BID, twice daily; BRCAm, breast cancer susceptibility gene mutation; CR, complete response; DCO, data cutoff; gBRCAm, germline breast cancer susceptibility gene mutation; HR, hazard ratio; ITT, intention to treat; NA, not available; NR, not reached; PFS, progression-free survival; PFS2, progression-free survival 2; OS, overall survival; ORR, objective response rate; PR, partial response; TDT, time to study treatment discontinuation or death; TFST, time to first subsequent therapy or death; TSST, time to second subsequent therapy or death.

Clinical interpretation:

Maintenance: Four trials investigated the efficacy of PARPi maintenance therapy in platinum-sensitive recurrent disease, and all showed an improvement in PFS.^11,17,19,23 Across all studies, women with a g/sBRCA mutation had the most robust clinical improvements. OS results just reported on the SOLO2 trial, which investigated olaparib monotherapy in patients with platinum-sensitive, recurrent, g/sBRCA1/2m EOC who had received ≥ 2 lines of chemotherapy. The preplanned, final, OS analysis with data maturity of 61% demonstrated that olaparib extended OS by approximately 13 months compared with placebo (38.8 v 51.7 months; HR, 0.74, 95% CI, 0.54 to 1.00; P = .054) in the full analysis set and extended OS by 15 months with olaparib compared with placebo (37.4 v 52.4 months; HR, 0.71; 95% CI, 0.52 to 0.97; P = .031) in the prespecified sensitivity analysis of patients with germline BRCA mutation.
Recurrent disease: The first approval for PARPis was for use in the treatment setting for recurrent ovarian cancer for PARPi-naïve women. Olaparib is FDA approved for the treatment of patients with gBRCAm ovarian, fallopian, or primary peritoneal cancer who have received ≥ 3 prior lines of chemotherapy. Rucaparib is approved for the treatment of patients with gBRCAm–associated ovarian, fallopian tube, or primary peritoneal cancer who have been treated with ≥ 2 chemotherapy regimens. Rucaparib yielded benefit in ARIEL2 ina small cohort (n = 5) of ovarian cancers with RAD51C or RAD51D mutations, with three PRs and two patients with prolonged stable disease for 8.3 and 11.0 months.²⁵

The recently reported, single-arm QUADRA trial of niraparib treatment in recurrent ovarian cancer met its primary end point demonstrating activity in fourth- and fifth-line treatment of patients with gBRCA and positive for HRD who were PARPi naïve and platinum sensitive to their last platinum therapy (n = 47). The study had an ORR of 28% and a median duration of response of 9.2 months. It was approved in 2019 for patients with advanced ovarian, fallopian tube, or primary peritoneal cancer treated with ≥ 3 prior chemotherapy regimens who are PARPi naïve and whose cancer is associated with HRD-positive status determined using the myChoice CDx as either tumor BRCA mutated and/or with a genomic instability score ≥ 42. Patients with HRD-positive cancers but without BRCA mutations must have experienced progression at least 6 months after the last dose of platinum-based therapy (ie, must have platinum-sensitive disease).

Dosing recommendations for treatment with all three agents are the same as defined previously for use in maintenance therapy. PARPi treatment is not generally recommended for treatment of platinum-resistant cancer. It has < 5% activity for treatment of BRCAwt, platinum-resistant, recurrent EOC. Any use of PARPi in the platinum-resistant setting is recommended to occur in the setting of a clinical trial, whether as a single agent or in chemotherapy, antiangiogenesis, or immunotherapy combinations. Nor should PARPis be readministered after prior exposure and progression on PARPi therapy, because there are no data to support that re-exposure in this setting is beneficial, and agent approval does not specify this option. Clinical trial participation is encouraged.

CLINICAL QUESTION 4

PARPi in Combination

Are there settings where a PARPi in combination with chemotherapy or other targeted therapy are recommended?

Recommendation 4.0

PARPis are not recommended for use in combination with chemotherapy, other targeted agents, or immune-oncology agents outside the context of a clinical trial. Clinical trial participation is encouraged (Type: informal consensus, benefits outweigh harms; Evidence quality: insufficient; Strength of recommendation: moderate).

Clinical interpretation.

There are limited data and numerous clinical trials now investigating the roles of PARPis in combination with chemotherapy, antiangiogenesis, or immunotherapies as treatment and in maintenance. The addition of PARPi is safe given no significant overlapping toxicity for women receiving hormonal blockade (ie, aromatase inhibitor) for synchronous breast cancer. However, there are no outcome data specific to this approach, to our knowledge. There is an increasing need to understand when and how to retreat with a PARPi, especially when there has been progression while receiving a prior PARPi. These unmet needs can only be clarified with well-designed randomized trials stratified for confounding elements such as g/sBRCA status, prior exposure to platinum agents, prior exposure to a PARPi, and accounting for AE risks. At this time, it is not recommended to re-treat with PARPi, even for patients with g/sBRCA platinum-sensitive disease, nor to use combination therapy not in a clinical trial.

CLINICAL QUESTION 5